Mixed lineage leukemia (MLL) presents a heterogeneous group of acute myeloid leukemia and acute lymphoblastic leukemia bearing features of more than one hematopoietic cell lineages. MLL accounts for about 80% of infant acute leukemia cases (Tomizawa, 2007; herein incorporated by reference in its entirety) and 10% of all acute leukemia cases (Marschalek, 2011; herein incorporated by reference in its entirety). Under current treatment protocols, MLL leukemia patients have a very poor prognosis with overall 5-year survival ratio stagnated around 35%, (Dimartino, 1999; Pui, 2003; Tomizawa, 2007; herein incorporated by reference in their entireties).
MLL is composited of heterogeneous cell lineages with different molecular biology, cell biology and immunology features. However, MLL does share a common feature, which involves the chromosomal rearrangement of Mixed Lineage Leukemia (MLL) gene. MLL gene locates on chromosome 11q23 and the encoded MLL protein is a homolog of Drosophila trithorax (Trx) (Tkachuk, 1992; herein incorporated by reference in its entirety). Wild type MLL binds to regulatory regions of homeox (HOX) genes (Milne, 2005; herein incorporated by reference in its entirety) through the amino terminal fragment while the catalytic C-terminal domain catalyzes the Histone 3 lysine 4 (H3K4) methylation and up regulates target genes transcription (Nakamura, 2002; Yokoyama, 2004; Milne, 2002; herein incorporated by reference in their entireties). Wild type MLL is required for maintenance HOX genes expression and is widely expressed not only during embryo development but also in adult tissues including myeloid and lymphoid cells (Butler, 1997; Yu, 1998; herein incorporated by reference in their entireties). Reciprocal translocations of MLL gene result in-frame fusion of 5′-end MLL with the 3′-end of another partner gene. Currently, more than 60 partner genes have been identified, with MLL-AF4, MLL-AF9 and MLL-ENL being the three most frequently found fusion genes (Pui, 2003; herein incorporated by reference in its entirety). Expression of MLL fusion proteins promotes over expression of target genes such as HOXA9 and MEIS1, which blocks differentiation, enhances blast expansion and ultimately leads to leukemic transformation (Caslini, 2007; Yokoyama, 2005; herein incorporated by reference in their entireties). Partial tandem duplication and MLL gene amplification present a small portion of MLL leukemia cases where no partner gene is involved. However, studies revealed that these genetic changes also lead to over expression of HOX or MEIS1 genes (Dorrance, 2006; Poppe, 2004; herein incorporated by reference in their entireties).
The numerous chromosomal translocation of MLL gene and partner genes diversity add to the complexity to MLL leukemia treatment, though HOX9 and MEIS1 overexpression are commonly observed among MLL leukemia patients, each rearrangement leading to distinct deregulated target genes expression pattern and downstream events (Slany, 2009; herein incorporated by reference in its entirety). Clinical researches suggested that MLL of different chromosomal translocation are associated with different prognosis and are treated differently under current protocols (Tamai, 2010; Balgobind, 2011; Pigazzi, 2011; herein incorporated by reference in their entireties). However, both wild type MLL and MLL fusion proteins retain N terminal domain, which contains the specific menin binding motifs (MBMs). Menin is a tumor repressor protein encoded by Multiple Endocrine Neoplasia 1 (MEN1) gene. The loss function of menin is closely tied with human neoplasms in multiple endocrine organs (Chandrasekharappa, 1997; herein incorporated by reference in its entirety). Menin is also a critical leukemogenic cofactor of MLL fusion proteins. MLL fusion protein with MBMs deletion is incapable of inducing leukemic transformation in progenitor cells (Yokoyama, 2005; herein incorporated by reference in its entirety). Expression of a dominant negative peptide representing the MBM region down-regulates Meis1 expression and inhibits MLL leukemic cells proliferation (Caslini, 2007; herein incorporated by reference in its entirety). Furthermore, depletion of menin results in acute down regulation of HOXA9 expression and revives differentiation in MLL leukemic cells (Yokoyama, 2004; Yokoyama, 2005; herein incorporated by reference in their entireties). In normal hematopoiesis, steady hematopoiesis is largely preserved in menin deficient mice (Maillard, 2009; Maillard, 2009; herein incorporated by reference in their entireties), providing a therapeutic window for MLL leukemia
The leukemogenic activity of MLL oncoproteins is dependent on association with menin. Therefore, selective targeting of this interaction could provide an attractive therapeutic approach to develop novel drugs for leukemias with translocations of MLL gene and other leukemias with upregulation of HOX genes.